Neurons avoid talking to themselves by using 19,000 forms of one gene

Neurons create functional networks in part by avoiding sending signals to …

A lot of effort has gone into exploring a key aspect of wiring the brain, the ability of nerve cells to form and maintain specific connections among the huge number of potential targets within the nervous system. Just as important, however, is the opposite question: how do these neurons avoid making inappropriate connections? Perhaps the most obvious form of inappropriate connection is the equivalent of a neural short-circuit, a case where a nerve cell forms connections to itself. Having a cell talking to itself could potentially cause all sorts of trouble in the brain, but neurons have a remarkable ability to recognize themselves and avoid making connections when they do.

Scientists have made some progress in identifying how this system works in flies over the last several years, and a new publication in the journal Cell takes that progress one step further by identifying how neuronal self-recognition works on the biochemical level. The study focuses on the gene Dscam, a cell surface molecule that genetics had previously identified as being critical for this process. At the gene level, Dscam has some very notable features: three places where its messenger RNA can be spliced together using any one of at least a dozen potential parts. All told, the combination of options at these three sites creates the potential for this one gene to encode over 19,000 distinct proteins.

Clearly, expressing any small subset of these possible protein forms would be enough to give a neuron a rough idea of its unique identity. The new research confirms the hypothesis that identity is registered by the fact that two DSCAM proteins are able to interact with each other provided they have the same combination of variable regions. The authors developed a high-throughput screen and used it to test over 18,000 potential forms of the DSCAM protein, finding that the vast majority are able to self-associate, while only about five percent of them can associate with any other form. Because of this specificity, it's easy for a cell to recognize when it's sticking to itself.

The authors also identified the key regions that mediate self association, and showed that small changes in these locations can have dramatic effects on binding specificity. They suggest that mutations that add additional protein forms capable of self-recognition should occur on a regular basis by duplicating a spliced region, and then having it pick up small mutations.

The research doesn't answer all of the questions about this system, as it's still unclear how splicing in different nerve cells is different enough to create all of the possible messenger RNAs that Dscam encodes. It also appears to be specific to flies; the mammalian Dscam equivalent can't make more than a few different proteins. So, even though we seem to know how the nerve cells of flies get a unique identity, it remains an open question of how the process happens in humans.

Cell, 2007. DOI: 10.1016/j.cell.2007.08.026

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